Endocrine Abstracts

Objectives: Endogenous Cushing’s syndrome (CS) is a rare, chronic condition that results in high morbidity, caused by prolonged exposure to elevated levels of circulating free cortisol. A previous comparative analysis showed osilodrostat increases the odds of complete response (CR; mean urinary free cortisol [mUFC] ≤ 1.0 x the upper limit of normal) at Weeks 12 and 36 vs metyrapone¹; however, analyses were limited by small osilodrostat effective sample size (ESS; 25 patients). Therefore, we used pooled osilodrostat data from the LINC-3 and LINC-4 clinical trials (n=185) to improve upon initial analyses of CR and discontinuation outcomes for osilodrostat vs metyrapone in CS.

Methods: The LINC-3/lINC-4 and PROMPT clinical trials investigated osilodrostat and metyrapone, respectively, in patients with endogenous CS. All LINC-3/lINC-4 patients and 90% of PROMPT patients had Cushing’s disease. Unanchored matching-adjusted indirect comparisons were conducted using pooled LINC-3 and LINC-4 patient-level data and published summary data for PROMPT. CR at Weeks 12, 24 and 36; all-cause discontinuation and discontinuation due to treatment failure at Weeks 24 and 36 were analysed. Six baseline characteristics, identified as potential prognostic factors, were adjusted for: age, sex, time since diagnosis, mUFC, prior irradiation and prior surgery. Scenario analyses adjusted for race and explored an alternative categorization of mUFC. Scenario analyses also investigated a range of plausible discontinuation rates for six patients ineligible to enter the 6-month PROMPT extension at Week 12, but not considered discontinuations in the primary analysis.

Results: Populations were well balanced after matching; the ESS for the matched pooled osilodrostat population was 76 patients. Results suggested osilodrostat provides increased odds of CR vs metyrapone at Week 12 (odds ratio [OR]: 2.75; 95% confidence interval [CI]: 1.29, 5.88), Week 24 (OR: 3.28; 95% CI: 1.58, 6.84) and Week 36 (OR: 10.50; 95% CI: 1.84, 59.96), implying a greater proportion of patients experience normalized cortisol levels at these timepoints. Results are statistically significant as 95% CIs exclude 1. No evidence of a statistically significant difference between treatments for the discontinuation endpoints was found. Scenario analyses (described above) had consistent results.

Conclusion: Our analyses suggest osilodrostat increases the odds of achieving CR at Weeks 12, 24 and 36 vs metyrapone, implying osilodrostat is a more efficacious treatment option than metyrapone for normalizing cortisol levels in CS patients. These analyses improve upon previous comparisons by substantially increasing the osilodrostat ESS, providing consistent and more reliable results.¹Tyas E, Endocr. abstr., 90. (2023) P132.